Yata Keiko, Bleuyard Jean-Yves, Nakato Ryuichiro, Ralf Christine, Katou Yuki, Schwab Rebekka A, Niedzwiedz Wojciech, Shirahige Katsuhiko, Esashi Fumiko
The Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Research Center for Epigenetic Disease, Graduate School of Frontier Sciences, University of Tokyo, Tokyo 113-0032, Japan; CREST, Japan Science and Technology Agency (JST), K's Gobancho, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
Cell Rep. 2014 Jun 12;7(5):1547-1559. doi: 10.1016/j.celrep.2014.04.023. Epub 2014 May 15.
Numerous human genome instability syndromes, including cancer, are closely associated with events arising from malfunction of the essential recombinase Rad51. However, little is known about how Rad51 is dynamically regulated in human cells. Here, we show that the breast cancer susceptibility protein BRCA2, a key Rad51 binding partner, coordinates the activity of the central cell-cycle drivers CDKs and Plk1 to promote Rad51-mediated genome stability control. The soluble nuclear fraction of BRCA2 binds Plk1 directly in a cell-cycle- and CDK-dependent manner and acts as a molecular platform to facilitate Plk1-mediated Rad51 phosphorylation. This phosphorylation is important for enhancing the association of Rad51 with stressed replication forks, which in turn protects the genomic integrity of proliferating human cells. This study reveals an elaborate but highly organized molecular interplay between Rad51 regulators and has significant implications for understanding tumorigenesis and therapeutic resistance in patients with BRCA2 deficiency.
包括癌症在内的许多人类基因组不稳定综合征都与关键重组酶Rad51功能异常引发的事件密切相关。然而，对于Rad51在人类细胞中如何受到动态调控却知之甚少。在此，我们表明乳腺癌易感蛋白BRCA2是Rad51的关键结合伴侣，它协调细胞周期核心驱动因子CDK和Plk1的活性，以促进Rad51介导的基因组稳定性控制。BRCA2的可溶性核部分以细胞周期和CDK依赖的方式直接结合Plk1，并作为一个分子平台促进Plk1介导的Rad51磷酸化。这种磷酸化对于增强Rad51与应激复制叉的结合很重要，进而保护增殖人类细胞的基因组完整性。这项研究揭示了Rad51调节因子之间复杂但高度有序的分子相互作用，对于理解BRCA2缺陷患者的肿瘤发生和治疗耐药性具有重要意义。
